Oral administration of a drug is the most convenient for the patient. Proper formulations must also meet the requirements of safety and simplicity. Depending on the properties of a drug and the therapeutic requirements different approaches must be taken during the formulation work to obtain the required delivery profile of the drug. Thus, sparingly soluble drugs to be given once a day require other types of formulations than easily soluble drugs to be taken several times a day. The matter has been discussed extensively in the literature and comprehensive reviews can be found, e g Langer and Wise (Eds) “Medical applications of controlled release”, vols I and II, CRC Press Inc, Boca Raton, 1984; Robinson and Lee (Eds) “Controlled drug delivery—fundamentals and applications”, Marcel Dekker, NY 1987; Bogeritoft and Sjögren, in “Towards better safety of drugs and pharmaceutical products” (Ed: Braimer), Elsevier, 1980; Sandberg “Extended-release metoprolol”, Thesis, Uppsala University, 1994.
Different formulations have different mechanisms controlling the release of the active substance. In the thesis by Sandberg 1994, extended-release (ER) formulations of different types of drugs are reviewed. It is concluded that in principle two types of ER dosage forms exist; the matrix system where the drug is mixed with the matrix material (often a polymer or a wax); and the drug reservoir system where the drug is formulated into a core (tablet or pellets) surrounded by a polymeric film. The film is then a release rate-controlling barrier determined by, e g its dissolution rate, its permeability, the solubility of the substance, etc.
From a flexibility point of view the formulation of a drug into small discrete units coated with a film has gained much attention. Such formulations show several interesting features, e g flexibility in dosage and modification of release properties, different dosage forms can be developed, dose size is adaptable to suit fixed combinations, tablets can be made divisible etc. In a number of studies it was shown that safe, simple, and convenient therapy could be achieved utilising this principle for the drug metoprolol and its salts (Ragnarsson et al, Drug Develop Ind Pharmacy 13, 1495 (1987); Sandberg et al, Eur J Clin Pharmacol 33, S3 (1988) and S9 (1988); Ragnarsson et al, Int J Pharmaceutics 79, 223 (1992); Sandberg et al, Ibid 68, 167 (1991); Sandberg et al, Pharmaceuticl Res 10, 28 (1993); Sandberg et al, Drug Invest 6, 320 (1993); Sandberg, Thesis Uppsala University, 1994).
The formulation of metoprolol into pellets according to the above mentioned references utilised a film coating sprayed from a solution of ethyl cellulose and hydroxypropyl methyl cellulose in an organic solvent. However, for environmental reasons it will be necessary in the near future to utilise water based film forming systems for this and other drugs to be formulated as pellet systems. Also, tablet coatings in general utilising organic solvents must for the same reasons be exchanged with water based film forming materials. Thus, much effort has been directed to find suitable water based systems for film coatings in drug delivery systems.
Latex particles in water as the dispersion medium have been known for almost half a century. These particles are polymeric colloidal particles in the 10 to 1000 nm range and have been utilised as film formers, e g in paints, in floor coatings, printing inks, adhesives etc. If the particle polymer has a sufficiently low glass transition temperature (Tg) when the water is evaporated, the particles can coalesce to form a film.
Water based film-forming polymer latexes for the pharmaceutical industry have been known since the early eighties when commercial dispersions more frequently appeared on the market (e g Aquacoat, FMC Corp.; Eudragit E-30D, Röhm Pharma). Further development has given several other products that have been tested and reported in a number of publications (Petereit and Weisbrod, Eur J Pharmaceutics and Biopharm 47, 15 (1999); Petereit et al, Ibid, 41, 219 (1995); Amighi and Moës, STP Pharma Sci 7, 141 (1997); Bodmeier and Paeratukul, Pharm Res 11, 882 (1994); Ozturk et al, J Controlled Release 14, 203 (1990). Goodhart et al, Pharmaceutical Tech April, 64 (1984); Bodmeier and Paeratakul Int J Pharmceutics 152, 17 (1997); Bodmeier and Paeratakul Drug Develop Ind Pharmacy 20, 1517 (1994)).
From these and other studies it can be concluded that one of the more interesting dispersions, due to the low Tg of the latex polymer, is Eudragit® NE30D, which contains approximately 28.5% w/w particles of the copolymer poly(ethylacrylate—co-methylmethacrylate), and 1.5% w/w of the non-ionic tenside Nonoxynol 100 (a polyoxyethylated nonylphenol) as the stabiliser. However, to obtain best spraying conditions and technical appearance of the film-coated pellets, an anti-sticking agent has to be added to the dispersion as reported by Petereit and Weisbrod 1995. One such agent is a glyceryl monostearate (GMS). It was also reported, however, that best performance of the dispersion during spraying and of the dried film was obtained when the GMS was dispersed with an extra surface active agent, e g polysorbate 80 (PS80). On the other hand, we have found that it has been difficult to obtain results with acceptable reproducibility with respect to, e g permeability and release rates from formulations manufactured according to these suggested procedures. One tentative explanation for this might be that the properties of the GMS/PS80 dispersion, e g size of dispersed particles, highly depend on process parameters like temperature, type of mixing etc, which also can be concluded from the results in the paper by Petereit and Weisbrod 1995.
Anti-sticking agents, also named detackifiers, glidants, and lubricants, are well-known agents used during pharmaceutical work. Similar substances have been used as anti-caking agents in food industry. The most commonly used substances for these purposes are, e g stearates, talc, polyethylene glycols, paraffines, lauryl sulphates, silica, and starches (M E Aulton (Ed) Pharmaceutics—the science of dosage form design Churchill Livingstone 1988; Susan Brewer Food Additives, document EHE-677 Illinois Co-operative Extension Service, 1994; M Ash and I Ash (Eds) Handbook of Pharmaceutical Additives, Gower Publishing Ltd, 1995). In connection with film-forming dispersions the most popular anti-sticking agents seem to be GMS, talc, and silica. However, in most of these latter applications reported these substances must first be dispersed with other added material, preferably surfactants or amphiphilic polymers to obtain more homogeneous systems.
Several patents or patent applications utilising these principles exist. Thus, Wolff et al, WO 00/13687; Wolff et al, WO 00/13686; Nagy et al, WO 99/42087; Lee et al, WO 99/30685; Eichel et al, U.S. Pat. No. 5,529,790; Eichel U.S. Pat. No. 5,478,573; Chen, U.S. Pat. No. 5,260,068; Petereit et al, EP 403,959; disclose the use of Eudragits for the (controlled) release of different types of drugs. In those applications when anti-sticking agents have to be used, combinations of surface active molecules and talc or stearates are most common. However, for our purposes these approaches are not attractive since several problems may arise due to, e g the combination of non-compatible materials, large amounts of extra dispersion additives, non-reproducibility during manufacturing, etc.
Sodium stearyl fumarate (sodium salt of 2-butenedioic monooctadecyl ester; Pruv™) is a pharmaceutical additive normally used as a lubricant for tabletting, where it in many cases can substitute and is superior to, e g magnesium stearate (Handbook of Pharmaceutical Excipients (Eds: A Wade and P J Weller) 2nd edition, Pharmaceutical Press, London 1994; A W Hözer and J Sjögren Int J Pharmaceutics 2, 145 (1979); G K Bolhuis and A W Hölzer in Pharmaceutical powder compaction technology (Eds G Aldeborn and C Nyström), Marcel Dekker Inc, NY 1995, chapter 16). Also, Pruv is approved for several food applications (Code of Federal Regulations, title 21, volume 3, part 172). Its solubility in water can be described by 1 g (solubility (gram Pruv/gram water))=0.057*T/(° C.)−5.7 according to the data given in the Handbook. Thus, at e g 60° C. the solubility is 0.005 gram per gram water. Further, its HLB value calculated according to the method by Davies (B Jönsson, B Lindman, K Holmberg, and B Kronberg Surfactants and polymers in aqueous solutions John Wiley & Sons, Chichester, 1998 p 353) amounts to about HLB=19.